The recent research from this laboratory provides direct evidencethat Drosophila is a suitable genetic model for studying molecular, cellular and neural basis of feeding behavioral control and eating disorders. We have shown that Drosophila neuropeptide F (NPF), the fly homologue of mammalian NPY, plays an important role in regulating hunger-driven foraging and feeding behaviors. Parallel behavioral phenotypes have been observed between NPF-deficient flies and NPY-knockoutmice: both animals were normal in baseline feeding and body weight control but displayed feeding deficits in the deprived state; NPF-deficient flies and NPY knockout mice also displayed decreased acute sensitivity to ethanol sedation. More recently, we have obtained evidence that analogous to mammalian insulin, Drosophila insulin-like peptides (DILPs) suppress feeding response by acting oh different neuronal networks including the NPY-like neuronal pathway. For example, DILPs appear to directly inhibit the signaling activity of NPFR1 neurons through the insulin-like receptor (lnR)/ribosomal S6 kinase (S6K) pathway. Taken together, our findings strongly suggest that signaling mechanisms for the regulation of foraging and feeding behaviors are largely conservedbetween flies and mammals. The proposed research aims to identify and characterize additional genes and molecular and neuronal pathways critical for hunger-driven behaviors. We are particularly interested in genes and neurons that differentially regulate distinct aspects of hunger response such as enhanced food seeking, motivated intake of less-preferred foods, and increased ingestion rate. The specific aims of this application include: 1) Analysis of genes and molecular pathways underlying the regulation of hunger-motivated foraging by NPFR1 neurons; 2) Analysis of genes and molecular pathways underlying the regulation of hunger-driven behaviors by DILP neurons; 3) Gain-of-function screen for genes critical for DILP/NPFR1 neuron-mediated hunger response. The results from these studies may provide general insights into how genetic and neural factors contribute to hunger regulation of food response in diverse organisms including mammals.